JPS62190144A - Antihypercholesterolemic compound - Google Patents

Abstract

Novel 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors which are useful as antihypercholesterolemic agents and are represented by the following general structural formulae (I) and (II):and pharmaceutically acceptable salts of the compounds (II) in which Z is hydrogen are disclosed.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention further relates to novel compounds useful as antihypercholesterolemic agents. In particular, the compounds of the invention are antihypercholesterolemic agents containing completely synthetic hydroxyalkyl analogs of biphenyl. Further disclosed are pharmaceutical compositions of these novel compounds both as sole therapeutically active ingredients and in admixture with bile acid sequestrants.

A specific HMG-COA reductase inhibitor of the present invention has the following general structural formula (1) and (1) (ID [where E is -CH2CH, -ma'fc is -CH=CH-; R1 , R2, R3, R4 and H5Fi independently hydrogen; halogen (F, α, Br or I); CI
-4 alkyl; CI-4 haloalkyl; hydroxy-CI-4 alkyl: C+-a alkanoyloxy〇,
-4 alkyl: Ca-12 aralkanoyloxy-C,
one. Alkyl; also oxy-C1-4 alkyl outside t'ict or CllZll; however, RI XR2
, R3, R4 or Rfi is selected from hydroxy-〇,-4 alkyl; C+-a alkanoyloxy-C1-4 alkyl; Cm-12 aralkanoyloxy-C1-4 alkyl; or C7 or Cllzll-exooxy-C1-4 alkyl; and 2 is hydrogen, C1-5 alkyl or substituted C1-5 alkyl consisting of phenyl, dimethylamino or acetylamino. ] It is a pharmaceutically acceptable salt of a compound represented by and a compound in which 2 is hydrogen.

One specific example of the present invention is a compound represented by formulas (1) and (■), in which E is CH2C)(2- or -CH=CH-, and R1 and R2 are independently c,-4 alkyl or hydroxy-CI-4 alkyl, and R3, R4 and R5 are independently hydrogen, fluoro, C1□
alkyl or hydroxy-01-4 alkyl, and 2 is a device consisting of hydrogen, CI-5 alkyl or phenyl, dimethylamino or acetylamino.
is a pharmaceutically acceptable salt of compound al) in which C,-5 alkyl and pl and 2 are hydrogen. One of the compounds of this specific example is a compound in which E in formula (1) and (2) is -CH=CH-. Examples of compounds of this type are those of formula (I) wherein R1 and R2 are independently methyl or hydroxymethyl, R3 is methyl or hydroxymethyl, R4 is fluoro, R5 is hydrogen or methyl, and 2 is hydrogen. and pharmaceutically acceptable salts thereof. A specific example of this type is trans-(E)-6-C2-C4'
-Fluoro-3'-1(hydroxymethyl)-3,5-dimethyl(1.1'-biphenyl]-2-yl]ethynyl) -3,4,5,6-tetrahydro-4-hydroxy-2H-bilane- 2-one and its corresponding free hydroxy acid.

Pharmaceutically acceptable salts of the invention include cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N '-dibenzylethylenediamine, chloropropylene, jetanolamine,
Includes salts formed from bases such as protriamine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane and tetramethylammonium hydroxide.

Compounds of formula (1) where E is -CH=CH- can be prepared from appropriately substituted cinnamaldehyde compounds (1) to U.S. Pat. No. 4,375,475 or U.S. Pat.
No. 22 or pending U.S. Patent Application No. 696
No. 963 (filing date January 31, 1985), Application No. 696965 (filing date January 31, 1985), or Application No. 741.069 (filing date June 4, 1985). They are conveniently prepared according to the following synthetic route utilizing general procedures.

R2(D E=-CH=CH- Cinnamaldehyde compound (1) (in the formula R6, R?, R
8, R9 and RIO are defined as R1, R2, R3, R4 and R5 respectively, but R1, R2, R3, R4
and when R5 is hydroxy-C,-4alkyl, the substituent is tri(C1-4alkyl)silyloxy-
0, -4 alkyl group, etc.) with a dianion of an acetoacetate ester, such as a methyl or ethyl ester, to form a hydroxy-ketoester. The resulting hydroxy-ketoester was then used in pending U.S. patent application Ser.
Stereospecific reduction using a trialkylborane and sodium borohydride in an alcoholic solvent using the general procedure described in Apr. 25, 1985). The resulting dihydroxy ester is saponified and lactonized under standard conditions to completely produce compound (2), treated with tetrabutylammonium fluoride under standard conditions to remove the tri(C1-4 alkyl)silyl protecting group, Generates a hydroxy C1-4 alkyl substituent present in compounds of formula (1) where E is -CH=CH-.

Compounds of formula (I) in which E is -CH,CH,-,
From compounds of formula (1) where CH=CH-, U.S. Pat.
．． 375.475 and 4.459.422 by reduction of the CH=CH- bridging group.

The production of cinnamaldehyde additives is described in U.S. Patent No. 4.37.
5.475 and 4.459.422 or pending U.S. patent application Ser.
No. 37.081 (filed August 1, 1984) by the nickel-catalyzed aryl cross-coupling operation described in US Pat. The C1-4 haloalkyl substituent can be replaced with an acetate anion before or after formation of this biphenyl moiety and then converted by hydrolysis to a hydroxy-C1-4 alkyl substitution. The hydroxy-C8-4 alkyl substituent was then replaced with dimethyl chloride-
Protected with a tri(CI-4alkyl)silyl halide such as tert-butylsilyl or reacted with a suitable carboxylic acid or acid halide to form C7-8furkayloxy-C1-4alkyl, Ca-1□ 7ralkanoyloxy"-C1-4 alkyl or C7 also produces a FiCI+70yloxy-C1-4 alkyl substituent.

Compounds of formula ■, or pharmaceutically acceptable salts thereof, which are z t3' hydrogens can be prepared by preparing suitable salts using mild basic hydrolysis of the lactone moiety of the compound of formula (1), careful acidification and standard procedures. Easily manufactured by generation.

Compounds of formula (1) in which Z is 01-, alkyl or substituted C1-, alkyl can be conveniently prepared by the procedures described in U.S. Pat. No. 4,342,767.

Resolution of the desired (+)-trans isomer of compounds of formula (I) is described in U.S. Pat.
This is accomplished using the general procedures described in No. 59.422.

The compounds of the present invention are useful as antihypercholesterolemic agents in the treatment of arteriosclerosis, hyperlipidemia, familial hypercholesterolemia, and similar diseases in humans. It can be administered orally or parenterally in the form of capsules, tablets, injection preparations, and the like. It is usually preferable to use the oral route. The dosage can be varied depending on the patient's (human) age, severity of symptoms, weight and other symptoms, but the daily dose for adults is about 2 to 200cm9 (preferably 20 to 100cm). can be administered in 2 to 4 divided doses. Advantageously, larger doses of ftff1 can be used as needed.

The compounds of the invention can also be co-administered with pharmaceutically acceptable, non-toxic cationic polymeric forms in the gastrointestinal tract. Examples of such polymers include cholestyramine, cholestibol and poly[methyl-(3-trimethylaminopropyl)imino-trimethylene dihalide]. The relative amounts of the compounds of the invention and these polymers are 1:
100 to 1:15,000.

The inherent HMG-COA reductase inhibitory activity of the claimed compounds is described in JlMed, Chem, Vol. 28,
347-358 (1985) and is described below.

Isolation of HMG-COA reductase Male Holtzmann-Sprague-Dawley rats (225-2
505') were kept in reverse lighting and sacrificed by C02 asphyxiation after 7 days of purinarat food containing 3% cholestyramine. Livers were removed to the dark circuit for 6 hours and immediately used to prepare microsomes.

HMG-CoA reductase was synthesized by Heller and Schleus IJ'-1) method [: J, Biol, Chem,
1976, Vol. 251, p. 3815] and the ammonium sulfate second precipitation step described by Kleinsek et al.
C1 Natl, Acad, Sci, USA I
977, Vol. 74, p. 1431]. Enzyme preparations) were tested for IMG-COA reductase titer and 100
Since the enzyme solution was diluted with mM salt buffer (p17.2), when added to the assay control, 100μtFi50.0 of the enzyme solution
00-60. OOOdl)m value was shown. The enzyme preparation was stored at -80°C.

) fMc; -CoA reductase inhibition assay The assay is essentially the procedure of Sheff 7 et al. (J, LipidReS, 1972, Vol. 13, p. 402). The complete medium for the assay is a total volume of Q.
, 8m/! Contains medium. phosphate buffer pr17
．． 2. 100mM, MgC/.

3mM NADP, 3mM glucose 6-phosphate.

10mM, glucose-6-phosphate dehydrogenase 3-unit, reduced glutathione, 50mM.

HMG-COA (glutaryl-3-140, New England Nucriano, 0.2 mM (0.1 μc
i) and partially purified enzyme raw material solution, 100μt0 test compound and compactin (initially INNa0H (1 equivalent ft
) was converted to the sodium salt in the dihydroxy acid form by the addition of 10μ of ) at various concentration levels to a volume of the assay system. After incubating at 37℃ for 40 minutes,
In order to complete the lactonization of mevalonic acid to mevalonolactone, 0.21 nl of the mixture was added to Fullpart et al. [J, p.
voC1Nat I, Acad, Sci, IJ,
S, A.

1980 Vol. 77, p. 3957], a 100-200 mesh Biolex 5, 0,5
Added to 5.0 crrL.

The unreacted [14C''l HMG-COA was absorbed into the resin, and the ['C) Kariinnolactone was dissolved in distilled water (2X 1 ml).
) directly into a 7 ml scintillation vial. Aqua True 2 and New England Nuclear) 5m
J1 was added to each vial, and the radioactivity was measured using a Paracard Tricar Purpurious Scintillation Counter. % inhibition was plotted against test compound concentration and quantified by fitting a straight line to the resulting data using the least squares method. The compactin value was designated as 100 to estimate the relative inhibitory potency, and the IC of the test compound. The values were compared with that of compactin, which was quantified at the same time.

Compound trans-(6)-6-C described in the claims
2-C4'-fluoro-3'-(hydroxymethyl)-
Typical unique H of 3,5-dimethyl[1,1'-biphenyl]-2-yl]ethynyl)-3,4,5,6-tetrahydro-4-hydroxy-2H-bilan-2-one
The MG-COA reductase inhibitory activity is 100 and has a relative potency of 26.5 compared to compactin.

The present invention provides a method for treating arteriosclerosis, familial hypercholesterolemia or hyperlipidemia, which comprises administering the compound of formula (I) or ■) or a pharmaceutical composition thereof to a patient in need of treatment. covered within the scope of the invention.

The following examples are merely illustrative of methods for preparing and incorporating compounds of formula (1) and (2) into pharmaceutical compositions and are not to be viewed as limitations on the claimed invention.

Example 1 trans-(odor-6-(:2-[:4'fluoro-3'
(Hydroxymethyl)-3,5-dimethyl[1,1'-
biphenyl]-2-yl]ethynyl'l-3,4,5,
6-tetrahydro-4-hydroxy-2H-bilan-2
(a) 4-Bromo-2-(bromomethyl)-1-fluorobenzene (1a) Irradiated with a 275 W UV-sun lamp and treated with N CCl2 (30 ml
) in 5-bromo-2-fluorotoluene (3,8y,
Cα4 (Br in 30 mI) was added to a refluxing solution of Br
t (1,11ill, 20mIJ mole) (7)
The solution was added dropwise. Reflux and irradiation were continued for an additional 0.5 h, then the clear pale yellow solution was concentrated. The residue was distilled to yield the desired compound (la)e as a clear colorless oil. bp 126-136℃ (1511III); N
MR4,38(2)1. S).

6.6-7.7 (3H, m).

(b) 2-(acetoxymethyl)-4-bromo-1-fluorobenzene (1b) Anhydrous sodium acetate (1,655', 20 mmol)
i Compound (la) (3 g) in DMF (25 ml).

14.6 mmol) and stirred on a steam bath under N2 for 11 hours. The reaction mixture was cooled and heated with N20 (2
00 ml> and E'20 (100 ntl).

The organic layer was separated, washed with N20 (3X 100ml), dried, filtered and evaporated to leave compound (1b) as an almost colorless oil.

NMR2.08 (3H,S), 5.08 (2H,S
), 6.7-7,9 (3H, m).

(C) 5-Bromo-2-fluorobenzyl alcohol (IC) compound (lb) (3,2f, 14.5 mmol), EtOH (20 m/) and lNNaOH (2
0 ml, 20 mmol) at reflux under N2.
Stir for hours.

Cool the reaction mixture and add H2o(x5od) and Et, o'
(15 ml). Separate the organic layer and evaporate with N20
(2X 10 oxl), dried and evaporated to a clear pale yellow solution. Distill the residue to obtain compound (IC)
' was produced as a clear colorless oil. bp82-87℃
(0,4a); NMR3,3(H,brs), 4.6(
2H,S), 6.81 (Hs.

t, J=9H2), 7.15~7.37 (H4,
m) 7.44 (Hb.

dd, J=3o and 6H2).

(d) 4-bromo-1-fluoro-2-(:(1,1-
dimethylethyl)dimethylsilyl]oxymethyl]benzene (1d) Compound (IC) (1,7?, in dry DMF (15 ml)
8.3 mmol), tert-butyldimethylsilyl chloride (1,8f, ], 2mm2mm) and imidazole (1,65', 24 mmol).
Stirred at 22° C. for 20 hours under Nt.

Pour into the mixed solution 'eH20 (200 m/), Et.

(2×75 rnl). Combine the organic extracts, INHC/(100ml), H,O(2X10
oIIL was washed with saturated NaHCO3 (100 ml), dried, filtered and evaporated. Remove the residual oil from silica gel (
Compound (ld) was obtained by chromatography with hexane).
' Generate t, "c. NMR0,1(6H,S), 0
．． 93 (9H, S), 4.73 (2H, S), 6
．． 82 (H8, t, J==9H2), 7.15~
7.37 (H,, m), 7.55 (Hb, dd
.

J=3 and 6H2). Analysis (CI3H211BrFO
8l)H calculated value C=48.90 11l constant value C=47.84 (c)(E)-3-(:4'-fluoro-3,5-dimethyl-3'-[1゜l-dimethylethyl )dimethylsilyl]oxymethyl:)[:1.1'-biphenylcy2
-yl]-2-propenonitrile (1e) Freshly prepared Grignard reagent (2, Or, 6.5 mmol) from compound (Id) in dry THF (6 ml) and magnesium turning (185 my, 7.
5 mm) L, ) f N2 Versi was filtered into a dry flask. ZnBr2 in THF (3A sieve drying, 2.5
2ml, 3.36 mmol) c7) 1.33
The M solution was added over 2 minutes with vigorous stirring. After about 5 minutes, 2-bromo-4,6-dimethylcinnamylnitrile (1,269,5,4 mmol) and bis(triphenylphosphine)nickel dichloride (100 mmol) were added.
g, 0.16 mmol) was added to the total gray slurry and the resulting reddish-brown mixture was heated at 35° C. under kN2.
Stirred for 5 hours. Reaction mixture '1lNHα (100m/
) and extracted into EtOAC (125 wtl). The organic phase was washed with HzO (2X 100ml), dried,
Filtration and evaporation left compound (1e) as a brown oil. The residual oil was purified by silica gel (EtOAC-hexane (1:
10)) to produce compound (1e). NMRo, 13 (6H,S), 0.9
4 (9H, S).

2,35 (3H,S), 2.42 (3H,S),
4.84 (2H, S).

5, 22 (H, d, J=l 7Hz), 6.98
~7.39 (6H, m).

(f) (E)-3-[4'-fluoro3,5-dimethyl-3'-[[(1,1-dimethylethyl)dimethylsilyl]oxymethyl)I:1. x'biphenyl]-2
-yl]-2-propanal (1f) in hexane (20% ) Medium jival (2.7ml,
3.2 mmol) solution was added over approximately 3 minutes. The cooling bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The mixture was cooled to about -10<0>C and quenched with 5% H, So4 (water cooling, 100 +++ A'). The Et,O solution was dried over MgSO4, evaporated and the residual yellow oil was chromatographed on silica gel (CH2C/,) to give compound (If)i as a pale yellow viscous oil. NMRo, 0
9 (6H, S).

0,91 (9H,S), 2.36 (3H,S),
2.46 (3H, S).

4,81 (2H,S), 6.19 (H,dd,
J=7 and H2).

6, 98-7.46 (6H, m), 9.45 (H
, d, J=7Hz).

(g) Methyl(t)-7-(4'-fluoro-3,5-
dimethyl-3'-[(d,1-dimethylethyl)dimethylsilyl]oxymethyl) C1,1'-biphenyl]
-2-yl]-3-hydroxy-5-oxo-6-hebutenoene A stirred suspension of sodium hydride (50% oil suspension) (11
0 m9.2.26 mmol) to methyl acetoacetate (24
3td, 2.26 mmol) was added dropwise. The resulting yellow solvent was stirred for an additional 15 minutes at 0°C, then anhydrous THp (
sm/) Medium attachment (1f) (0,83f!, 2.09
mmol) solution. Obtained orange solvent 1o℃
The mixture was stirred for 15 minutes and then quenched by dropwise addition of INHα (5 ml). The reaction mixture was diluted with N20 (100ml) and extracted into Et20 (150ml). The organic layer was separated, washed with H,O (2X 100ml) and washed with Mg
Dried with SO4 and filtered. The P solution was evaporated in vacuo to leave compound (12) as a deep yellow color (1.olr,
cz%). NMRo, 137(6H,S), 0.94
8 (9H,S), 2.337 (3H,S).

2,343 (3H,S), 2.578 (2H,d
d), 3.455 (2H,S), 3.737 (
3H,S), 4.548 (H,m).

4,822 (2H, m), 5.306 (H, dd
, J=7 and 16 N2), 6.489 (H
, d, J=16H2), 6.97~7, 42 (6
H, m).

(11) Methyl(6)-7-(4'-fluoro-3,5
-dimethyl-3'-1: [(x,x-dimethylethyl)
dimethylsilyl]oxymethyl)(],,]t'-biphenyl]-2-yl]3,5-dihydroxy-6-heptenoate (1h) compound (1g) (1,oy,
1.96 mmol) in dry THF (5 ml) under N2
After dissolving in triethylbora:/(1 M in THF
, 2.9 ml, 2.9 mmol). After aging for 5 minutes, the reaction mixture was heated to -98°C (MeOH solution N2
(bath). Addition of sodium borohydride (85m9°2.25mmol) followed by MeOH (2ml)
was added for 5 minutes. After stirring for an additional 0.5 h, the reaction mixture 'i- was warmed to 60°C and then N
20 (10ml>30% H2O2 in 4ml) f
Quench by careful addition. After vigorously stirring the mixture at room temperature for 0.5 hour, IN) Iα (50 ml
) and EtoAc (10 Oml). The organic layer was washed with N20 (2X 50ml), dried, filtered and evaporated to yield compound (1h) as a pale yellow gum. 'HNMR shows an erythro to threo ratio of 11:1.

NMRo, 12 (6H,S), 0.93 (9H,S
), 1.42-1.61 (2H.

m), 2.32 (CiH,S), 2.34-2
．． 46 (2H, m).

3,70 (3H,S), 4.05-4.15 (H
, m), 4.3-4, 4(H, m), 4.7-4.
85 (2H, mL 5.29 (H.

dd, J=7 and I 6H2), 6.43 (H,
d, J=16Hz).

5, 5Q (H, d, J = 16 N2).

(i) trans-(odor-6-1:2-[4'-fluoro-3,5-dimethyl-3'-[:C(1,1-dimethylethyl)dimethylsilyl]oxymethyl] (1,1 '
-biphenyl]-2-yl]ethynyl: ]-3,4,5
,6-tetra-hydro-4-hydroxy-2H-bilan-2-o compound (lh) (900m9.1.7miI
JMo/L).

A solution of IN NaOH (2-5at, 2.5 mmol) and MeOH (15 ml) was stirred at 25 °C for 1 h.

The reaction mixture was evaporated in vacuo at 25 °C and the residue was evaporated with N20
(100ml). The reaction solvent was 12NHCl (
The mixture was acidified with E'20 (100 ml) and extracted with E'20 (100 ml). The organic extract was washed with iH,O (2×100 ml), dried over MgSO4, filtered, evaporated and the remaining dihydroxy acid was dissolved in toluene (75 ml) and heated at reflux in a Dean-Stark apparatus. After 3 hours, the toluene was removed in vacuo, leaving the crude compound (1) as a deep yellow color. The oil was chromatographed on silica gel. CN2Cl! HPLC "Whatman Verticil PXS" eluted with 2-acetone (19:], V=V).
Elution time 3,7 on a 10/2'5 PAC column using 10% isopropyl/hexane at a flow rate of in//min.
2 minutes yielded homogeneous compound (li)' as a pale yellow oil. NMRo, 139 (6H,s
), o, 946 (9H, S).

1, 61-1.84 (2H, m), 2.345 (
6) (,S), 2.45-2,75 (2H,m),
3.947-3.994 (H, m), 4.81
(2H.

m), 5.096-5.134 (H, m), 5.3
0 (H, dd, J = 7 and 16 N2), 6
．． 50 (H, d, J=16H2), 6.938-7
, 338 (6H, m).

(j) trans(t))-6-(2-(4'-fluoro-3'-(hydroxymethyl)-3,5-dimethyl(1
,1'-biphenyl]-2-yl]ethynyl 3-3.4
．． 5. Compound (l) in 6-tetrahydro-4-hydroxy-2H-bilan-2-one T) (F (F) ml)
i) A solution of (420 m9° 0.087 mmol) was dissolved in ammonium fluoride (IM in THF, 2.5 μt, 2.
5 mmol). After stirring at 20°C for 5 minutes,
INHα (100m7?) was added and the product (i-El
, O (125 ml). The organic layer was heated with H20 (2
x 100 ml), dried, P:A and evaporated to TLC ["Rfo for silyl ether, 20:0.42 (silica, CHα, -Meon (19:
1))] and HPLC (Whatman Perticil PX
20% isopropano-JV on S10/2 SPAC column
Elution time was 5.36 minutes using hexane at a flow rate of 4 rtrl 7 minutes] to yield the homogeneous desired compound as a pale yellow gum. Analytical samples were crystallized with n13uα. mp137-138°C; NMRl, 7-1.95
(2H, m), 2.33 (6H, S), 2.4
5-2.75 (2H, m), 4.05-4.1 (H
, m), 4.7-4.85 (2H, m).

5, 12-5.1s (H, m), 5.4 (H, d
d, , y = 7 and 15H2), 6.53 (H
, d, J=15Hz), 6.95-7.35 (6
H.

m).

Examples 2-10 The following compounds were prepared from appropriately substituted shishinamilnitrile using the general procedure of Example 1.

2 CH20HcH,CH,F H3CH
,C120HCH,F H4CH,CH3CH2
0HHCH.

5 CH, CH20HCH, HCH36CH20
HCH, CH, HCH.

7 CH, CH5CH20HHCH580H, C
H, CH20CC(CH3), F H9C2H,
C,H40HCH,F Hlo C,H
, C, Xin C, H40I (F ) (Example 11 Production of alkali and alkaline earth salts of compound ■x9/
To a solution of the lactone of Example 1 (j) (42 mg) in 2 ml) was added aqueous NaOH (1 eq.). After 1 hour at room temperature, the mixture was dried in vacuo to yield the sodium salt of compound (1).

In a similar manner, potassium salt 'i was prepared using 1 equivalent of potassium hydroxide, and calcium salt was prepared using 1 equivalent of CaO.

Example 12 Preparation of the methyl ester of compound H To a solution of ~400 of the lactone of Example 1(d) in 10 o II 11 of anhydrous methanol was added 10 mt of 0.1M sodium methoxide in anhydrous methanol. The solution was left at room temperature for 1 hour, then diluted with water, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and the ethyl acetate was removed in vacuo to produce the methyl ester of compound (1).

In a similar manner, use of isopropyl alcohol, butanol, isobutanol, t-butanol, amyl alcohol, isoamyl alcohol, 2-dimethylaminoethanol, benzyl alcohol, phenethanol, 2-7cetamidoethanol, etc. The corresponding ester was obtained by

Example 13 Preparation of free hydroxy acid The sodium salt of compound (2) of Example (1) was dissolved in ethanol-water (
The hydroxy acid was extracted with ethyl acetate. The latter solvent was washed once with water, dried and removed in vacuo using a bath temperature not exceeding 30°C. Gradually, the resulting hydroxy acid reverted to a lactone upon standing.

Example 4 As a specific embodiment of the composition of the invention, the lactone 20InO of Example 10) was formulated with sufficiently finely divided lactose to produce a total volume of 580-590 m and filled into size 0 hard gelatin capsules. .

Applicant: Merck & Co., Ltd.

Claims (1)

[Claims] 1 The following general structural formula (I) or (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I)▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, E is -CH_2CH_2- or -CH=CH-, and R^1, R^2, R^3, R^4 and R^5 are independently hydrogen, halogen, C_1_-_4 alkyl, C_1_-
_4 haloalkyl, hydroxy-C_1_-_4 alkyl, C_1_-_8 alkanoyloxy-C_1_-_
4 alkyl, C_8_-_1_2 aralkanoyloxy-C_1_-_4 alkyl or C_7 or C_1_
1aroyloxy-C_1_-_4 alkyl, provided that at least one of R^1, R^2, R^3, R^4 or R^5 is hydroxy-C_1_-_4 alkyl,
C_1_-_8 alkanoyloxy-C_1_-_4 alkyl, C_8_-_1_2 aralkanoyloxy-C
selected from _1_-_4 alkyl or C_7 or C_1_1aroyloxy-C_1_-_4 alkyl;
Z is hydrogen, C_1_-_5 alkyl or C_1_-_5 alkyl substituted with a group selected from phenyl, dimethylamino, acetylamino. ) or a pharmaceutically acceptable salt of the compound (II) in which Z is hydrogen. 2 E is -CH_2CH_2- or -CH=CH- and R^1 and R^2 are independently C_1_-_4 alkyl or hydroxy-C_1_-_4 alkyl,
R^3, R^4 and R^5 are independently hydrogen, fluoro,
C_1_-_4 alkyl or hydroxy-C_1_-
The compound according to claim 1, which is _4. 3. The compound according to claim 2, wherein E is -CH=CH-. 4 R^1 and R^2 are independently methyl or hydroxymethyl, R^3 is methyl or hydroxymethyl, and R^4
is fluoro, R^5 is hydrogen or methyl, and Z is hydrogen, or a pharmaceutically acceptable salt thereof. 5 trans-(E)-6-[2-[4'fluoro-3
'-(Hydroxymethyl)-3,5-dimethyl [1,1
'-biphenyl]-2-yl]ethenyl-3,4,5,
6-tetrahydro-4-hydroxy-2H-bilan-2
-one or its corresponding free hydroxy acid. 6 (+)-Trans isomer Claim 1
Compounds described in Section. 7. A pharmaceutical composition comprising a non-toxic hypocholesterolemic, hypolipidemic amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 8 The therapeutically effective ingredient is trans-(E)-6-[2-
[4'-fluoro-3'-(hydroxymethyl)-3,
A claim that is 5-dimethyl[1,1'-biphenyl]-2-yl]ethenyl-3,4,5,6-tetrahydro-4-hydroxy-2H-bilan-2-one or its corresponding free hydroxy acid The pharmaceutical composition according to item 7. 9. The pharmaceutical composition according to claim 7, wherein the therapeutically effective ingredient is the (+)-trans isomer. 10 (a) Formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^6, R^7, R^8, R^9, R^1^0 are R^1 and R^, respectively. 2, R^3, R^4, and R^5, but at least one of R^6, R^7, R^8, R^9, or R^1^0 is a bird (C_1_- ＿４
alkyl)silyloxy-C_1_-_4 alkyl group. ) is treated with tetrabutylammonium fluoride to produce a compound of formula (I); (b) optionally the silyl ether precursor to step (a) is treated with dihydrobyran to form a tetrahydrofylene compound; The biranyl ether is generated, followed by treatment with tetrabutylammonium fluoride, followed by reaction with the appropriate acyl halide, followed by removal of the tetrahydroviranyl protecting group in dilute aqueous acid to form the substituents R^1, R One of ^2, R^3, R^4 or R^5 is C_1_-_8 alkanoyloxy-C_1_-_4
Alkyl or C_8_-_1_2 aralkanoyloxy-C_1_-_4 alkyl or C_7 or C_1
(c) optionally treating the compound from step (a) or step (b) under suitable basic conditions to form a compound of formula (I) which is _1aroyloxy-C_1_-_4alkyl; (II) and (d) optionally treating the salt from step (c) under acidic conditions to produce a compound of formula (II) in which Z is H. The following general structural formula (I) or (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I)▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (E in the formula is -CH_2CH_2 or -CH =CH- and R
^1, R^2, R^3, R^4 and R^5 are independently hydrogen, halogen, C_1_-_4 alkyl, C_1_-_
4-haloalkyl, hydroxy-C_1_-_4 alkyl, C_1_-_8 alkanoyloxy-C_1_-_4
Alkyl, C_8_-_1_2 aralkanoyloxy-
C_1_-_4 alkyl or C_7 or C_1_1
Aroyloxy-C_1_-_4 alkyl, provided that at least one of R^1, R^2, R^3, R^4 or R^5 is hydroxy-C_1_-_4 alkyl, C_
1_-_8 alkanoyloxy-C_1_-_4 alkyl, C_8_-_1_2 aralkanoyloxy-C_1
selected from ____4 alkyl or C_7 or C_1_1aroyloxy-C_1__4 alkyl, and Z is hydrogen. ) A method for producing a pharmaceutically acceptable salt of a compound represented by the following table or a compound (II) in which Z is hydrogen.